Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives

ABSTRACT

A method for treating hair loss in mammals uses compositions containing 2-decarboxy-2-phosphinico prostaglandin derivatives. The compositions can be applied topically to the skin. The compositions can arrest hair loss, reverse hair loss, and promote hair growth. Compositions containing 2-decarboxy-2-phosphinico prostaglandin derivatives can also be used to lower intraocular pressure and treat bone disorders.

FIELD OF THE INVENTION

This invention relates to compositions and methods for using2-decarboxy-2-phosphinico derivatives of prostaglandins. Moreparticularly, this invention relates to the use of2-decarboxy-2-phosphinico derivatives of prostaglandins for treatinghair loss in mammals. This invention further relates to the use of2-decarboxy-2-phosphinico derivatives of prostaglandins for loweringintraocular pressure and treating bone disorders in mammals.

BACKGROUND OF THE INVENTION Hair Loss—Cosmetic Treatment

Hair loss is a common problem which is, for example, naturally occurringor chemically promoted through the use of certain therapeutic drugsdesigned to alleviate conditions such as cancer. Often such hair loss isaccompanied by lack of hair re-growth which causes partial or fullbaldness.

Hair growth on the scalp does not occur continuously, but rather occursby a cycle of activity involving alternating periods of growth and rest.This cycle is divided into three main stages; anagen, catagen, andtelogen. Anagen is the growth phase of the cycle and is characterized bypenetration of the hair follicle deep into the dermis with rapidproliferation of cells which are differentiating to form hair. The nextphase is catagen, which is a transitional stage marked by the cessationof cell division, and during which the hair follicle regresses throughthe dermis and hair growth ceases. The next phase, telogen, ischaracterized as the resting stage during which the regressed folliclecontains a germ with tightly packed dermal papilla cells. At telogen,the initiation of a new anagen phase is caused by rapid cellproliferation in the germ, expansion of the dermal papilla, andelaboration of basement membrane components. When hair growth ceases,most of the hair follicles reside in telogen and anagen is not engaged,thus causing the onset of full or partial baldness.

Attempts to invoke the re-growth of hair have been made by, for example,the promotion or prolongation of anagen. Currently, there are two drugsapproved by the United States Food and Drug Administration for thetreatment of male pattern baldness: topical minoxidil (marketed asROGAINE® by Pharmacia & Upjohn), and oral finasteride (marketed asPROPECIA® by Merck & Co., Inc.). However, the search for efficacioushair growth inducers is ongoing due to factors including safety concernsand limited efficacy.

The thyroid hormone thyroxine (“T4”) converts to thyronine (“T3”) inhuman skin by deiodinase 1, a selenoprotein. Selenium deficiency causesa decrease in T3 levels due to a decrease in deiodinase I activity; thisreduction in T3 levels is strongly associated with hair loss. Consistentwith this observation, hair growth is a reported side effect ofadministration of T4. See, e.g., Berman, “Peripheral Effects ofL-Thyroxine on Hair Growth and Coloration in Cattle”, Journal ofEndocrinology, Vol. 20, pp. 282-292, (1960); and Gunaratnam, “TheEffects of Thyroxine on Hair Growth in the Dog”, J. Small Anim. Pract.,Vol. 27, pp. 17-29 (1986). Furthermore, T3 and T4 have been the subjectof several patent publications relating to treatment of hair loss. See,e.g., Fischer et al., DE 1,617,477, published Jan. 8, 1970; Mortimer, GB2,138,286, published Oct. 24, 1984; and Lindenbaum, WO 96/25943,assigned to Life Medical Sciences, Inc., published Aug. 29, 1996.

Unfortunately, however, administration of T3 or T4, or both, to treathair loss is often not practicable because these thyroid hormones caninduce significant cardiotoxicity. See, e.g., Walker et al., U.S. Pat.No. 5,284,971, assigned to Syntex, issued Feb. 8, 1994 and Emmett etal., U.S. Pat. No. 5,061,798, assigned to Smith Kline & FrenchLaboratories, issued Oct. 29, 1991.

In an alternative approach, prostaglandins have been proposed to promotehair growth because prostaglandins may have a similar benefit to thyroidhormones, i.e., increasing hair length and changing pigmentation.Naturally occurring prostaglandins (e.g., PGA₂, PGB₂, PGE₁, PGF_(2α),and PGI₂) are C-20 unsaturated fatty acids. PGF_(2α), the naturallyoccurring Prostaglandin F analog in humans, is characterized by hydroxylgroups at the C9 and C11 positions on the alicyclic ring, a cis-doublebond between C5 and C6, and a trans-double bond between C13 and C14.PGF_(2α) has the formula:

Analogs of naturally occurring Prostaglandin F are known in the art. Forexample, see U.S. Pat. No. 4,024,179 issued to Bindra and Johnson on May17, 1977; German Patent No. DT-002,460,990 issued to Beck, Lerch,Seeger, and Teufel published on Jul. 1, 1976; U.S. Pat. No. 4,128,720issued to Hayashi, Kori, and Miyake on Dec. 5, 1978; U.S. Pat. No.4,011,262 issued to Hess, Johnson, Bindra, and Schaaf on Mar. 8, 1977;U.S. Pat. No. 3,776,938 issued to Bergstrom and Sjovall on Dec. 4, 1973;P. W. Collins and S. W. Djuric, “Synthesis of Therapeutically UsefulProstaglandin and Prostacyclin Analogs”, Chem. Rev., Vol. 93, pp.1533-1564 (1993); G. L. Bundy and F. H. Lincoln, “Synthesis of17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG₁ Series”,Prostaglandin, Vol. 9, No. 1, pp. 14 (1975); W. Bartman, G. Beck, U.Lerch, H. Teufel, and B. Scholkens, “Luteolytic Prostaglandin: Synthesisand Biological Activity”, Prostaglandin, Vol. 17, No. 2, pp. 301-311(1979).

Prostaglandins in general have a wide range of biological activities.For example, PGE₂ has the following properties: a) regulator of cellproliferation, b) regulator of cytokine synthesis, c) regulator ofimmune responses and d) inducer of vasodilatation. Vasodilatation isthought to be one of the mechanisms of how minoxidil provides a hairgrowth benefit. In vitro results in the literature also indicate someanti-inflammatory properties of the prostaglandins. c.f.; Tanaka, H., BrJ. Pharm., 116, 2298, (1995).

However, previous attempts at using prostaglandins to promote hairgrowth have been unsuccessful. Different prostaglandins can bind tomultiple receptors at various concentrations with a biphasic effect.Therefore, it is an object of this invention to provide methods forusing prostaglandins to grow hair and to provide compositions thatpromote hair growth. It is a further object of this invention to providea selection of appropriate prostaglandins that will promote hair growthin humans and lower animals.

Bone Disorders—Pharmaceutical Treatment

In addition to the biological activities discussed above, prostaglandinsare also known to affect bone. Therefore, it is a further object of thisinvention to provide compositions and methods for using prostaglandinsto treat bone disorders.

Accelerated bone loss may result from drug administration, such ascorticosteroids, prolonged bed rest, disuse of a limb, and microgravity.In osteoporotics, an imbalance in the bone remodeling process developsin which bone is resorbed at a rate faster than it is being made.Although this imbalance occurs to some extent in most individuals, maleand female, as they age, it is more severe and occurs at a younger agein osteoporotics, particularly those who develop the post menopausalform of the condition. Bone loss due to the above conditions can resultin complete removal of trabeculae and a deterioration of bonearchitecture such that the strength of the remaining bone decreasesdisproportionately.

To completely return the bone to normal strength, new trabeculae shouldbe formed to restore architecture and increase bone mass. Whenrestoration of normal architecture is associated with an increase instrength and return to normal stiffness and shock absorbing capability,the bone is less likely to fracture. Subjects suffering from other bonedisorders, such as osteoarthritis, Paget's disease, periodontal disease,and fractures may also benefit from treatments that restore normalarchitecture and bone mass.

Various agents have been tried in attempts to treat bone disorders byslowing bone loss or increasing bone mass. Agents for slowing bone lossand reestablishing bone density are exemplified by antiresorptive agentssuch as bisphosphonates.

Prostaglandin E analogs are potent stimulators of bone resorption andformation. Anabolic agents such as some prostaglandin E analogs may bedetrimental to one suffering from bone disorders such as osteoporosisbecause increased resorption may cause perforation and loss oftrabeculae or may weaken the exsting trabecular structure. Increasedresorption may also occur in cortical bone, which may increase theincidence of fracture at some sites.

Anabolic agents such as fluoride and other prostaglandin E analogs havebeen used to increase bone mass. However, such agents have failed tobuild bone that is structurally and architecturally similar to the typeof bone lost.

Naturally occurring PGF_(2α), shown above, is also known to affect boneresorption. However, naturally occurring prostaglandins have severaldrawbacks that limit their desirability for systemic administration.Naturally occurring prostaglandins are characterized by their activityat a certain prostagladin receptor, however, their activity is notlimited to any one receptor. Therefore, systemic administration ofnaturally occurring prostaglandins can cause side effects such asinflammation, surface irritation, smooth muscle contraction, pain, andbronchoconstriction.

Therefore, it is an object of this invention to provide compositions andmethods using prostaglandins to treat bone disorders without significantundesirable side effects. It is a further object of this invention toprovide a selection of appropriate prostaglandins that will promote bonegrowth in humans and lower animals.

Intraocular Pressure—Pharmaceutical Treatment

In addition to the pharmacological properties discussed above, naturallyoccurring prostaglandins are also known to reduce intraocular pressure.Reduction of intraocular pressure is effective to treat disorders suchas glaucoma. See C. Iiljebris, G. Selen, B. Resul, J. Sternschantz, andU. Hacksell, “Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin F₂α.Isopropyl Ester: Potential Antiglaucoma Agents”, Journal of MedicinalChemistry, Vol. 38, No. 2, pp. 289-304 (1995). However, as discussedabove, the naturally occurring prostaglandins generally are not specificfor any one prostaglandin receptor, and thus are known to cause sideeffects.

Therefore, it is an object of this invention to provide compositions andmethods using prostaglandins to lower intraocular pressure withoutsignificant undesirable side effects. It is a further object of thisinvention to provide a selection of appropriate prostaglandins that willlower intraocular pressure in humans and lower animals.

SUMMARY OF THE INVENTION

This invention relates to compositions and methods for treating hairloss. The methods comprise administering the compositions comprisingspecific prostaglandins that interact strongly with hair-selectivereceptors, such as the FP receptor. The choice of prostaglandin isimportant because the prostaglandin must selectively activate the FPreceptor and not activate any other receptors that would negate theeffect of activating the FP receptor or that would cause significantundesirable side effects. The prostaglandins used in this invention are2-decarboxy-2-phosphinico derivatives of prostaglandins. This inventionfurther relates to the use of 2-decarboxy-2-phosphinico derivatives ofprostaglandins to prepare compositions for treating hair loss. Thecompositions comprise: component A) the 2-decarboxy-2-phosphinicoderivative of a prostaglandin, component B) a carrier, and optionallycomponent C) an activity enhancer.

This invention further relates to compositions and methods for treatingbone disorders. The methods comprise administering, to subjectssuffering from bone disorders such as osteoporosis, compositionscomprising 2-decarboxy-2-phosphinico derivatives of prostaglandins. Thisinvention further relates to the use of 2-decarboxy-2-phosphinicoderivatives of prostaglandins to prepare compositions for treating bonedisorders.

This invention further relates to compositions and methods for loweringintraocular pressure. The methods comprise administering, to subjectssuffering from conditions such as glaucoma, compositions comprising2-decarboxy-2-phosphinico derivatives of prostaglandins. This inventionfurther relates to the use of 2-decarboxy-2-phosphinico derivatives ofprostaglandins to prepare compositions for lowering intraocularpressure.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, this invention relates to compositions for treating hairloss in mammals. “Treating hair loss” includes arresting hair loss orreversing hair loss, or both, and promoting hair growth.

Publications and patents are referred to throughout this disclosure. AllU.S. patents cited herein are hereby incorporated by reference.

All percentages, ratios, and proportions used herein are by weightunless otherwise specified.

Definition and Usage of Terms

The following is a list of definitions for terms, as used herein:

“Activate” means binding and signal transduction of a receptor.

“Acyl group” means a monovalent group suitable for acylating a nitrogenatom to form an amide or carbamate, an alcohol to form a carbonate, oran oxygen atom to form an ester group. Preferred acyl groups includebenzoyl, acetyl, tert-butyl acetyl, para-phenyl benzoyl, andtrifluoroacetyl. More preferred acyl groups include acetyl and benzoyl.The most preferred acyl group is acetyl.

“Aromatic group” means a monovalent group having a monocyclic ringstructure or fused bicyclic ring structure. Monocyclic aromatic groupscontain 5 to 10 carbon atoms, preferably 5 to 7 carbon atoms, and morepreferably 5 to 6 carbon atoms in the ring. Bicyclic aromatic groupscontain 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in thering. Aromatic groups are unsubstituted. The most preferred aromaticgroup is phenyl.

“Carbocyclic group” means a monovalent saturated or unsaturatedhydrocarbon ring. Carbocyclic groups are monocyclic, or are fused,spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic groupscontain 4 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and morepreferably 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic groupscontain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in thering. Carbocyclic groups are unsubstituted. Preferred carbocyclic groupsinclude cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl. More preferred carbocyclic groups include cyclohexyl,cycloheptyl, and cyclooctyl. The most preferred carbocyclic group iscycloheptyl. Carbocyclic groups are not aromatic.

“Cyano group” means a group containing a nitrile functionality.

“FP agonist” means a compound that activates the FP receptor.

“FP receptor” means known human FP receptors, their splice variants, andundescribed receptors that have similar binding and activation profilesas the known human FP receptors. “FP” means the receptor is of the classwhich has the highest affinity for PGF_(2α) of all the naturallyoccurring prostaglandins. FP refers to a known protein.

“Halogen atom” means F, Cl, Br, or I. Preferably, the halogen atom is F,Cl, or Br; more preferably Cl or F; and most preferably F.

“Halogenated heterogenous group” means a substituted heterogenous groupor a substituted heterocyclic group, wherein at least one substituent isa halogen atom. Halogenated heterogenous groups can have a straight,branched, or cyclic structure. Preferred halogenated heterogenous groupshave 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and mostpreferably 1 to 3 carbon atoms. Preferred halogen atom substituents areCl and F.

“Halogenated hydrocarbon group” means a substituted monovalenthydrocarbon group or a substituted carbocyclic group, wherein at leastone substituent is a halogen atom. Halogenated hydrocarbon groups canhave a straight, branched, or cyclic structure. Preferred halogenatedhydrocarbon groups have 1 to 12 carbon atoms, more preferably 1 to 6carbon atoms, and most preferably 1 to 3 carbon atoms. Preferred halogenatom substituents are Cl and F. The most preferred halogenatedhydrocarbon group is trifluoromethyl.

“Heteroaromatic group” means an aromatic ring containing carbon and 1 to4 heteroatoms in the ring. Heteroaromatic groups are monocyclic or fusedbicyclic rings. Monocyclic heteroaromatic groups contain 5 to 10 memberatoms (i.e., carbon and heteroatoms), preferably 5 to 7, and morepreferably 5 to 6 in the ring. Bicyclic heteroaromatic rings contain 8to 12 member atoms, preferably 9 or 10 in the ring. Heteroaromaticgroups are unsubstituted. Preferred heteroaromatic groups includethienyl, thiazolyl, purinyl, pyrimidyl, pyridyl, and furanyl. Morepreferred heteroaromatic groups include thienyl, furanyl, and pyridyl.The most preferred heteroaromatic group is thienyl.

“Heteroatom” means an atom other than carbon in the ring of aheterocyclic group or the chain of a heterogeneous group. Preferably,heteroatoms are selected from the group consisting of nitrogen, sulfur,and oxygen atoms. Groups containing more than one heteroatom may containdifferent heteroatoms.

“Heterocyclic group” means a saturated or unsaturated ring structurecontaining carbon and 1 to 4 heteroatoms in the ring. No two heteroatomsare adjacent in the ring. Heterocyclic groups are not aromatic.Heterocyclic groups are monocyclic, or are fused or bridged bicyclicring systems. Monocyclic heterocyclic groups contain 4 to 10 memberatoms (i.e., including both carbon atoms and at least 1 heteroatom),preferably 4 to 7, and more preferably 5 to 6 in the ring. Bicyclicheterocyclic groups contain 8 to 12 member atoms, preferably 9 or 10 inthe ring. Heterocyclic groups are unsubstituted. Preferred heterocyclicgroups include piperzyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl, and piperdyl.

“Heterogeneous group” means a saturated or unsaturated chain containing1 to 18 member atoms (i.e., including both carbon and at least oneheteroatom). No two heteroatoms are adjacent. Preferably, the chaincontains 1 to 12 member atoms, more preferably 1 to 6, and mostpreferably 1 to 4. The chain may be straight or branched. Preferredbranched heterogeneous groups have one or two branches, preferably onebranch. Preferred heterogeneous groups are saturated. Unsaturatedheterogeneous groups have one or more double bonds, one or more triplebonds, or both. Preferred unsaturated heterogeneous groups have one ortwo double bonds or one triple bond. More preferably, the unsaturatedheterogeneous group has one double bond. Heterogeneous groups areunsubstituted.

“Monovalent hydrocarbon group” means a chain of 1 to 18 carbon atoms,preferably 1 to 12 carbon atoms. “Lower monovalent hydrocarbon group”means a monovalent hydrocarbon group having 1 to 6, preferably 1 to 4carbon atoms. Monovalent hydrocarbon groups may have a straight chain orbranched chain structure. Preferred monovalent hydrocarbon groups haveone or two branches, preferably 1 branch. Preferred monovalenthydrocarbon groups are saturated. Unsaturated monovalent hydrocarbongroups have one or more double bonds, one or more triple bonds, orcombinations thereof. Preferred unsaturated monovalent hydrocarbongroups have one or two double bonds or one triple bond; more preferredunsaturated monovalent hydrocarbon groups have one double bond.

“Pharmaceutically acceptable” means suitable for use in a human or othermammal.

“Prostaglandin” means a fatty acid derivative which has a variety ofpotent biological activities of a hormonal or regulatory nature.

“Protecting group” is a group that replaces the active hydrogen of ahydroxyl moiety thus preventing undesired side reaction at the hydroxylmoiety. Use of protecting groups in organic synthesis is well known inthe art. Examples of protecting groups are found in Chapter 2 ProtectingGroups in Organic Synthesis by Greene, T. W. and Wuts, P. G. M., 2^(nd)ed., Wiley & Sons, Inc., 1991. Preferred protecting groups include silylethers, alkoxymethyl ethers, tetrahydropyranyl, tetrahydrofuranyl,esters, and substituted or unsubstituted benzyl ethers.

“Safe and effective amount” means a quantity of a prostaglandin highenough to provide a significant positive modification of the subject'scondition to be treated, but low enough to avoid serious side effects(at a reasonable benefit/risk ratio).

“Selective” means having a binding or activation preference for aspecific receptor over other receptors which can be quantitated basedupon receptor binding or activation assays.

“Subject” means a living vertebrate animal such as a mammal (preferablyhuman) in need of treatment.

“Substituted aromatic group” means an aromatic group wherein 1 to 4 ofthe hydrogen atoms bonded to carbon atoms in the ring have been replacedwith other substituents. Preferred substituents include: halogen atoms,cyano groups, monovalent hydrocarbon groups, substituted monovalenthydrocarbon groups, heterogeneous groups, aromatic groups, substitutedaromatic groups, or any combination thereof. More preferred substituentsinclude halogen atoms, monovalent hydrocarbon groups, and substitutedmonovalent hydrocarbon groups. Preferred substituted aromatic groupsinclude naphthyl. The substituents may be substituted at the ortho,meta, or para position on the ring, or any combination thereof. Thepreferred substitution pattern on the ring is ortho or meta. The mostpreferred substitution pattern is ortho.

“Substituted carbocyclic group” means a carbocyclic group wherein 1 to 4hydrogen atoms bonded to carbon atoms in the ring have been replacedwith other substituents. Preferred substituents include: halogen atoms,cyano groups, monovalent hydrocarbon groups, monovalent heterogeneousgroups, substituted monovalent hydrocarbon groups, aromatic groups,substituted aromatic groups, or any combination thereof. More preferredsubstituents include halogen atoms and substituted monovalenthydrocarbon groups. Carbocyclic group does not include aromatic rings.

“Substituted heteroaromatic group” means a heteroaromatic group wherein1 to 4 hydrogen atoms bonded to carbon atoms in the ring have beenreplaced with other substituents. Preferred substituents include:halogen atoms, cyano groups, monovalent hydrocarbon groups, substitutedmonovalent hydrocarbon groups, heterogeneous groups, substitutedheterogeneous groups, phenyl groups, phenoxy groups, or any combinationthereof. More preferred substituents include halogen atoms, halogenatedhydrocarbon groups, halogenated heterogenous groups, monovalenthydrocarbon groups, and phenyl groups.

“Substituted heterocyclic group” means a heterocyclic group wherein 1 to4 hydrogen atoms bonded to carbon atoms in the ring have been replacedwith other substituents. Preferred substituents include: halogen atoms,cyano groups, monovalent hydrocarbon groups, substituted monovalenthydrocarbon groups, heterogeneous groups, substituted heterogeneousgroups, halogenated hydrocarbon groups, halogenated heterogenous groups,phenyl groups, phenoxy groups, or any combination thereof. Morepreferred substituents include halogen atoms and halogenated hydrocarbongroups. Substituted heterocyclic groups are not aromatic.

“Substituted heterogeneous group” means a heterogeneous group, wherein 1to 4 of the hydrogen atoms bonded to carbon atoms in the chain have beenreplaced with other substituents. Preferred substituents include halogenatoms, hydroxy groups, alkoxy groups (e.g., methoxy, ethoxy, propoxy,butoxy, and pentoxy), aryloxy groups (e.g., phenoxy, chlorophenoxy,tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, andacyloxyphenoxy), acyloxy groups (e.g., propionyloxy, benzoyloxy, andacetoxy), carbamoyloxy groups, carboxy groups, mercapto groups,alkylthio groups, acylthio groups, arylthio groups (e.g., phenylthio,chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, andalkyloxycarbonylphenylthio), aromatic groups (e.g., phenyl and tolyl),substituted aromatic groups (e.g., alkoxphenyl, alkoxycarbonylphenyl,and halophenyl), heterocyclic groups, heteroaromatic groups, and aminogroups (e.g., amino, mono- and di-alkylamino having 1 to 3 carbon atoms,methylphenylamino, methylbenzylamino, alkanylamido groups of 1 to 3carbon atoms, carbamamido, ureido, and guanidino).

“Substituted monovalent hydrocarbon group” means a monovalenthydrocarbon group wherein 1 to 4 of the hydrogen atoms bonded to carbonatoms in the chain have been replaced with other substituents. Preferredsubstituents include halogen atoms; halogenated hydrocarbon groups;halogenated heterogenous groups; alkyl groups (e.g., methyl, ethyl,propyl, and butyl); hydroxy groups; alkoxy groups (e.g., methoxy,ethoxy, propoxy, butoxy, and pentoxy); aryloxy groups (e.g., phenoxy,chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy,alkyloxycarbonylphenoxy, and acyloxyphenoxy); acyloxy groups (e.g.,propionyloxy, benzoyloxy, and acetoxy); carbamoyloxy groups; carboxygroups; mercapto groups; alkylthio groups; acylthio groups; arylthiogroups (e.g., phenylthio, chlorophenylthio, alkylphenylthio,alkoxyphenylthio, benzylthio, and alkyloxycarbonylphenylthio); arylgroups (e.g., phenyl, tolyl, alkoxyphenyl, alkoxycarbonylphenyl, andhalophenyl); heterocyclyl groups; heteroaryl groups; and amino groups(e.g., amino, mono- and di-alkanylamino groups of 1 to 3 carbon atoms,methylphenylamino, methylbenzylamino, alkanylamido groups of 1 to 3carbon atoms, carbamamido, ureido, and guanidino).

Prostaglandins Used in the Invention

The prostaglandins suitable for use in this invention are selected fromthe group consisting of 2-decarboxy-2-phosphinico derivatives ofprostaglandins; optical isomers, diastereomers, and enantiomers of the2-decarboxy-2-phosphinico derivatives; pharmaceutically-acceptable saltsof the 2-decarboxy-2-phosphinico derivatives; and biohydrolyzableamides, esters, and imides of the 2-decarboxy-2-phosphinico derivatives.

Suitable 2-decarboxy-2-phosphinico derivatives can have a formulaselected from the group consisting of:

R¹ is selected from the group consisting of a hydrogen atom, lowermonovalent hydrocarbon groups, lower substituted monovalent hydrocarbongroups, and lower heterogeneous groups. R¹ is preferably selected fromthe group consisting of a hydrogen atom; an alkyl group such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl; ahalogenated hydrocarbon group such as trifluoromethyl or CH₂CH₂CF₃;CH₂CH₂OH, and CH₂CH₂CH₂OH. More preferably, R¹ is a hydrogen atom,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,trifluoromethyl, CH₂CH₂CF₃, CH₂CH₂OH, or CH₂CH₂CH₂OH. Most preferably,R¹ is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, or CH₂CH₂OH.

R² is selected from the group consisting of a hydrogen atom, amonovalent hydrocarbon group, a substituted monovalent hydrocarbongroup, a heterogeneous group, a substituted heterogeneous group, acarbocyclic group, a substituted carbocyclic group, a heterocyclicgroup, a substituted heterocyclic group, an aromatic group, asubstituted aromatic group, a heteroaromatic group, and a substitutedheteroaromatic group. Preferably R² is H, CH₂CO₂H, CH₂C(O)NHOH, methyl,CF₃, ethyl, n-propyl, isopropyl, CH₂CH₂OH, CH₂CH(OH)CH₂OH, benzyl, ort-butyl. More preferably, R² is H, methyl, CF₃, ethyl, n-propyl,isopropyl, CH₂CH₂OH, CH₂C(O)NHOH, and benzyl. Most preferably, R² is H,methyl, CF₃, ethyl, n-propyl, isopropyl, or CH₂CH₂OH.

R³ is selected from the group consisting of an oxygen atom, a sulfuratom, and NH. Preferably, R³ is an oxygen atom or NH; more preferably,R³ is an oxygen atom.

R⁴ is selected from the group consisting of an oxygen atom and a sulfuratom. Preferably, R⁴ is an oxygen atom.

R⁵ is a divalent group. R⁵ is selected from the group consisting of ahydrocarbon group, a substituted hydrocarbon group, a heterogeneousgroup, and a substituted heterogeneous group. R⁵ may be saturated orunsaturated, i.e., R⁵ may contain one or more single bond, double bond,triple bond, or combinations thereof. When R⁵ is a heterogeneous group,R⁵ has only one heteroatom, which is selected from the group consistingof oxygen, sulfur, and nitrogen. The preferred heteroatom is oxygen. R⁵preferably has 1 to 5 member atoms, more preferably 3 to 5 member atoms.

Bond a is selected from the group consisting of a single bond, a transdouble bond, and a triple bond.

R⁶ is a divalent group selected from the group consisting of —C(O)— and—C(R⁹)(OR⁹)—.

R⁷ is selected from the group consisting of a divalent group having theformula —(CR⁹(R⁹))_(p)—X—(CR⁹(R⁹))_(q), wherein p is an integer from 0to 3 and q is an integer from 0 to 3, and wherein X is selected from thegroup consisting of an oxygen atom, a divalent hydrocarbon group, asulfur atom, SO, SO₂, and NR⁹. Preferably, X is selected from the groupconsisting of a single bond, a trans double bond, a triple bond, anoxygen atom, a sulfur atom, and NR⁹.

R⁸ is selected from the group consisting of a methyl group, acarbocyclic group, a substituted carbocyclic group, a heterocyclicgroup, a substituted heterocyclic group, aromatic group, a substitutedaromatic group, a heteroaromatic group, a substituted heteroaromaticgroup. When R⁸ is a monocyclic group, it has 5 to 10 member atoms. WhenR⁸ is a bicyclic group, it has 8 to 12 member atoms. Preferably, R⁸ isselected from the group consisting of a monocyclic carbocyclic group, asubstituted monocyclic carbocyclic group, a monocyclic heterocyclicgroup, a substituted monocyclic heterocyclic group, aromatic group, asubstituted aromatic group, a heteroaromatic group, and a substitutedheteroaromatic group.

R⁹ is a hydrogen atom or a lower monovalent hydrocarbon group.Preferably, R⁹ is a hydrogen atom.

R¹⁰ is a hydrogen atom or a lower monovalent hydrocarbon group.Preferably, R¹⁰ is a hydrogen atom.

Component A) may also be any optical isomer, diastereomer, andenantiomer of any of the above structures; or anypharmaceutically-acceptable salts of any of the above structures; or anybiohydrolyzable amides, esters, and imides of any of the abovestructures; or combinations thereof.

The prostaglandin used in this invention preferably has the formula:

wherein, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and bond a are as describedabove. More preferably, R⁹ is a hydrogen atom.

Suitable prostaglandins for component A) can be prepared by conventionalorganic syntheses. Examples of suitable prostaglandins for component A)can be prepared by the following reaction scheme.

In the reaction scheme above, R¹, R², R⁵, R⁶, R⁷, R⁸, R⁹, and bond a areas described above, X is a halogen atom, and Q and Q² are protectinggroups. The Corey Lactone (S1a) starting material is commerciallyavailable (from Aldrich Chemical Company or Cayman Chemical Company).Known Wadsworth-Horner-Emmons chemistry is used to attach the bottomchain of the desired prostaglandin to the Corey Lactone, creatingcompounds of the type S1b. There follows standard prostaglandin omegachain manipulation and functional group protection, including optionalalkene reduction, which creates compounds of type S1c. At this point,the standard course of prostaglandin synthesis is altered; theomega-functionalized Wittig reagent depicted is used to create2-decarboxy prostaglandin derivatives of the type S1d. When thecarboxycyclic acid containing prostaglandin is available, compounds ofthe type S1d are also obtained by a one-carbon degradation using amodification of the Hunsdiecker reaction.

Compounds depicted by S1e are available from compounds of the type S1dvia a phosphinite coupling reaction with an alkyl diethyloxyphosphinite,which is obtained, as shown, from the chlorodiethyloxyphosphine reagent,which is commercially available. Compounds depicted by Formula III areavailable from compounds of the type S1e via optional removal of thealkene and subsequent removal of the protecting groups Q and Q² of S1e.

Alternatively, compounds of the type S1f can be prepared fromintermediate S1e, where the protecting groups Q and Q² are judiciouslyselected from a variety available to those skilled in the art (see, forexample: Protecting Groups in Organic Synthesis by Greene, T. W. andWuts, P. G. M., 2^(nd) ed., Wiley & Sons, Inc., 1991). Subsequentremoval of Q at C11, followed by oxidation would give the ketoneprecursor to S1f. Compounds of the type S1f can then be obtained byfinal deprotection.

Compounds of Formula I can be prepared from compounds of formula S1f bycondensation with hydroxyl amine. Compounds of Formula II can be reducedto prepare compounds of Formula I by treatment with sodiumcyanoborohydride in THF:acetic acid (1:1) and thereafter quenching withHCl. Using conventional organic synthesis techniques, one skilled in theart could prepare prostaglandins suitable for use in this invention.

Examples of suitable prostaglandins of Formula I include Formula 1A.Formula 1A is TABLE 1A

Substituents in Formula 1A R⁹ R¹ R⁷ R⁸ H CH₃ CH₂S

H CH₂CH₃ CH₂S

H CH₃ CH₂O

H CH₃ CH₂CH₂CH₂CH₂ CH₃ H CH₃ CH₂CH₂CH₂CH₂CH₂ CH₃ H CH₃ CH₂O

H CH₃ CH₂NH

CH₃ CH₃ CH₂CH₂CH₂CH₂ CH₃ H CH₂CH₃ CH₂S

H CH₂CH₂CH₂CH₃

wherein R¹, R⁷, R⁸, and R⁹, are defined in Table IA.

Examples of suitable prostaglandins of Formula II include Formula 2A.Formula 2A is TABLE 2A

Substituents in Formula 2A b a R¹ R⁷-R⁸ cis trans CH₃

single single CH₃

single single CH₂CH₃

single single CH₂CH₃

cis trans CH₂CH₃

single single CH(CH₃)₂

wherein a, b, R¹, and R⁷-R⁸ are defined in Table 2A.

Examples of suitable prostaglandins of Formula III include Formulae 3Aand 3B. Formula 3A is TABLE 3A

Substituents in Formula 3A R¹ R⁷ R⁸ CH₃ CH₂CH₂

CH₃ CH₂S

CH₃ CH₂O

CH₂CH₃ CH₂O

CH₂CH₃ CH₂O

CH₂CH₂CH₃ CH₂CH₂

CH₃ CH₂NH

CH₃ CH₂NH

CH₃ CH₂ CH₂ CH₂CH₂ CH₃ CH₂CH₃ CH₂

CH₃ CH₂O

CH₃ CH₂CH═CHCH₂ CH₃ CH₃ CH₂O

CH₂CH₂CH₃ CH₂CH₂

CH₃ CH₂

CH₂CH₃ CH₂O

wherein R¹, R⁷, and R⁸ are defined in Table 3A.

Formula 3B is TABLE 3B

Substituents in Formula 3B R¹ R⁷ R⁸ CH₃ CH₂S

CH₂CH₃ CH═CH

CH₃

CH₃ —CH═C═CH—

CH₃ CH₂S

CH₃ CH₂O

CH₂CH₃ CH₂O

CH₃ CH₂CH₂

CH₃ CH₂NH

H CH₂NH

wherein R¹, R⁷, and R⁸ are defined in Table 3B.

Compositions of the Invention Hair Loss

This invention further relates to a composition for treating hair loss.“Treating hair loss” means arresting hair loss, reversing hair loss, orboth, and promoting hair growth. The composition comprises A) the PGFdescribed above and B) a carrier. The composition may further compriseC) one or more optional activity enhancers.

The composition can be a pharmaceutical or cosmetic composition,administered for treatment or prophylaxis of hair loss. Standardpharmaceutical formulation techniques are used, such as those disclosedin Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Penn. (1990).

The composition further comprises component B) a carrier. “Carrier”means one or more compatible substances that are suitable foradministration to a mammal. Carrier includes solid or liquid diluents,hydrotopes, surface-active agents, and encapsulating substances.“Compatible” means that the components of the composition are capable ofbeing commingled with the prostaglandins, and with each other, in amanner such that there is no interaction which would substantiallyreduce the efficacy of the composition under ordinary use situations.Carriers must be of sufficiently high purity and sufficiently lowtoxicity to render them suitable for administration to the mammal beingtreated. The carrier can be inert, or it can possess pharmaceuticalbenefits, cosmetic benefits, or both, depending on the intended use asdescribed herein.

The choice of carrier for component B) depends on the route by which A)the prostaglandin will be administered and the form of the composition.The composition may be in a variety of forms, suitable, for example, forsystemic administration (e.g., oral, rectal, nasal, sublingual, buccal,or parenteral) or topical administration (e.g., local application on theskin, ocular, liposome delivery systems, or iontophoresis). Topicaladministration directly to the locus of desired hair growth ispreferred.

Carriers for systemic administration typically comprise one or moreingredients selected from the group consisting of a) diluents, b)lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g)sweeteners, h) antioxidants, j) preservatives, k) glidants, m) solvents,n) suspending agents, o) surfactants, combinations thereof, and others.

Ingredient a) is a diluent. Suitable diluents include sugars such asglucose, lactose, dextrose, and sucrose; polyols such as propyleneglycol; calcium carbonate; sodium carbonate; glycerin; mannitol;sorbitol; and maltodextrin.

Ingredient b) is a lubricant. Suitable lubricants are exemplified bysolid lubricants including silica, talc, stearic acid and its magnesiumsalts and calcium salts, calcium sulfate; and liquid lubricants such aspolyethylene glycol and vegetable oils such as peanut oil, cottonseedoil, sesame oil, olive oil, corn oil and oil of theobroma.

Ingredient c) is a binder. Suitable binders includepolyvinylpyrrolidone; magnesium aluminum silicate; starches such as cornstarch and potato starch; gelatin; tragacanth; and cellulose and itsderivatives, such as sodium carboxymethylcellulose, ethylcellulose,methylcellulose, microcrystalline cellulose, andhydroxypropylmethylcellulose; carbomer; providone; acacia; guar gum; andxanthan gum.

Ingredient d) is a disintegrant. Suitable disintegrants include agar,alginic acid and the sodium salt thereof, effervescent mixtures,croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starchglycolate, clays, and ion exchange resins.

Ingredient e) is a colorant such as an FD&C dye.

Ingredient f) is a flavor such as menthol, peppermint, and fruitflavors.

Ingredient g) is a sweetener such as saccharin and aspartame.

Ingredient h) is an antioxidant such as butylated hydroxyanisole,butylated hydroxytoluene, and vitamin E.

Ingredient j) is a preservative such as phenol, alkyl esters ofparahydroxybenzoic acid, benzoic acid and the salts thereof, boric acidand the salts thereof, sorbic acid and the salts thereof, chorbutanol,benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate,nitromersol, benzalkonium chloride, cetylpyridinium chloride, methylparaben, and propyl paraben. Particularly preferred are the salts ofbenzoic acid, cetylpyridinium chloride, methyl paraben and propylparaben, and sodium benzoate.

Ingredient k) is a glidant such as silicon dioxide.

Ingredient m) is a solvent, such as water, isotonic saline, ethyloleate, alcohols such as ethanol, glycerin, glycols (e.g., polypropyleneglycol and polyethylene glycol), and buffer solutions (e.g., phosphate,potassium acetate, boric carbonic, phosphoric, succinic, malic,tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric,and glutamic).

Ingredient n) is a suspending agent. Suitable suspending agents includeAVICEL® RC-591 from FMC Corporation of Philadelphia, Penn. and sodiumalginate.

Ingredient o) is a surfactant such as lecithin, polysorbate 80, sodiumlauryl sulfate, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene monoalkyl ethers, sucrose monoesters, lanolin esters,and lanolin ethers. Suitable surfactants are known in the art andcommercially available, e.g., the TWEENS® from Atlas Powder Company ofWilmington, Del.

Compositions for parenteral administration typically comprise A) 0.1 to10% of a prostaglandin and B) 90 to 99.9% of a carrier comprising a) adiluent and m) a solvent. Preferably, component a) is propylene glycoland m) is ethanol or ethyl oleate.

Compositions for oral administration can have various dosage forms. Forexample, solid forms include tablets, capsules, granules, and bulkpowders. These oral dosage forms comprise a safe and effective amount,usually at least 5%, and preferably from 25% to 50%, of A) theprostaglandin. The oral dosage compositions further comprise B) 50 to95% of a carrier, preferably 50 to 75%.

Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed. Tablets typicallycomprise A) the prostaglandin, and B) a carrier comprising ingredientsselected from the group consisting of a) diluents, b) lubricants, c)binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, k)glidants, and combinations thereof. Preferred diluents include calciumcarbonate, sodium carbonate, mannitol, lactose, and sucrose. Preferredbinders include starch, and gelatin. Preferred disintegrants includealginic acid, and croscarmelose. Preferred lubricants include magnesiumstearate, stearic acid, and talc. Preferred colorants are the FD&C dyes,which can be added for appearance. Chewable tablets preferably containg) sweeteners such as aspartame and saccharin, or f) flavors such asmenthol, peppermint, and fruit flavors.

Capsules (including time release and sustained release formulations)typically comprise A) the prostaglandin, and B) a carrier comprising oneor more a) diluents disclosed above in a capsule comprising gelatin.Granules typically comprise A) the prostaglandin, and preferably furthercomprise k) glidants such as silicon dioxide to improve flowcharacteristics.

The selection of ingredients in the carrier for oral compositionsdepends on secondary considerations like taste, cost, and shelfstability, which are not critical for the purposes of this invention.One skilled in the art can optimize appropriate ingredients withoutundue experimentation.

The solid compositions may also be coated by conventional methods,typically with pH or time-dependent coatings, such that A) theprostaglandin is released in the gastrointestinal tract at various timesto extend the desired action. The coatings typically comprise one ormore components selected from the group consisting of cellulose acetatephthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulosephthalate, ethyl cellulose, acrylic resins such as EUDRAGIT® coatings(available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes,shellac, polyvinylpyrrolidone, and other commercially availablefilm-coating preparations such as Dri-Klear, manufactured by Crompton &Knowles Corp., Mahwah, N.J. or OPADRY® manufactured by Colorcon, Inc.,of West Point, Penn.

Compositions for oral administration can also have liquid forms. Forexample, suitable liquid forms include aqueous solutions, emulsions,suspensions, solutions reconstituted from non-effervescent granules,suspensions reconstituted from non-effervescent granules, effervescentpreparations reconstituted from effervescent granules, elixirs,tinctures, syrups, and the like. Liquid orally administered compositionstypically comprise A) the prostaglandin and B) a carrier comprisingingredients selected from the group consisting of a) diluents, e)colorants, and f) flavors, g) sweeteners, j) preservatives, m) solvents,n) suspending agents, and o) surfactants. Peroral liquid compositionspreferably comprise one or more ingredients selected from the groupconsisting of e) colorants, f) flavors, and g) sweeteners.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as a) diluents including sucrose, sorbitol and mannitol; and c)binders such as acacia, microcrystalline cellulose,carboxymethylcellulose, and hydroxypropylmethylcellulose. Suchcompositions may further comprise b) lubricants, e) colorants, f)flavors, g) sweeteners, h) antioxidants, and k) glidants.

The compositions for treating hair loss may further comprise componentC) an optional activity enhancer. Component C) is preferably selectedfrom the group consisting of i) hair growth stimulants (other than theprostaglandin) and ii) penetration enhancers.

Component i) is an optional hair growth stimulant. Component i) isexemplified by vasodilators, antiandrogens, cyclosporins, cyclosporinanalogs, antimicrobials, anti-inflammatories, thyroid hormones, thyroidhormone derivatives, and thyroid hormone analogs, non-selectiveprostaglandin agonists or antagonists, retinoids, triterpenes,combinations thereof, and others. “Non-selective prostaglandin” agonistsand antagonists differ from component A) in that they do not selectivelyactivate the FP receptor, and they may activate other receptors.

Vasodilators such as potassium channel agonists including minoxidil andminoxidil derivatives such as aminexil and those described in U.S. Pat.Nos. 3,382,247, 5,756,092, 5,772,990, 5,760,043, 5,466,694, 5,438,058,4,973,474, and cromakalin and diazoxide can be used as optional hairgrowth stimulants in the composition.

Examples of suitable antiandrogens include 5-α-reductase inhibitors suchas finasteride and those described in U.S. Pat. No. 5,516,779, and inNane et al., Cancer Research 58, “Effects of Some Novel Inhibitors ofC17,20-Lyase and 5α-Reductase in vitro and in vivo and Their PotentialRole in the Treatment of Prostate Cancer,” as well as cyproteroneacetate, azelaic acid and its derivatives and those compounds describedin U.S. Pat. No. 5,480,913, flutamide, and those compounds described inU.S. Pat. Nos. 5,411,981, 5,565,467, and 4,910,226.

Antimicrobials include selenium sulfide, ketoconazole, triclocarbon,triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol,mipirocin and those described in EPA 0,680,745, clinacycinhydrochloride, benzoyl peroxide, benzyl peroxide and minocyclin.

Examples of suitable anti-inflammatories include glucocorticoids such ashydrocortisone, mometasone furoate and prednisolone, nonsteroidalanti-inflammatories including cyclooxygenase or lipoxygenase inhibitorssuch as those described in U.S. Pat. No. 5,756,092, and benzydamine,salicylic acid, and those compounds described in EPA 0,770,399,published May 2, 1997, WO 94/06434, published Mar. 31, 1994, and FR2,268,523, published Nov. 21, 1975.

3,5,3′-Triiodothyronine is an example of a suitable thyroid hormone.

Examples of suitable non-selective prostaglandins agonists andantagonists include compounds such as those described in WO 98/33497,Johnstone, published Aug. 6, 1998, WO 95/11003, Sternschantz, publishedApr. 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.

Suitable retinoids include isotretinoin, acitretin, and tazarotene.

Other optional hair growth stimulants for component i) includebenzalkonium chloride, benzethonium chloride, phenol, estradiol,chlorpheniramine maleate, chlorophyllin derivatives, cholesterol,salicylic acid, cysteine, methionine, red pepper tincture, benzylnicotinate, DL—menthol, peppermint oil, calcium pantothenate, panthenol,castor oil, prednisolone, resorcinol, chemical activators of proteinkinase C, glycosaminoglycan chain cellular uptake inhibitors, inhibitorsof glycosidase activity, glycosaminoglycanase inhibitors, esters ofpyroglutamic acid, hexosaccharic acids or acylated hexosaccharic acids,aryl-substituted ethylenes, N-acylated amino acids, flavinoids,ascomycin derivatives and analogs, histamine antagonists such asdiphenhydramine hydrochloride, triterpenes such as oleanolic acid andursolic acid and those described in U.S. Pat. Nos. 5,529,769, 5,468,888,5,631,282, and 5,679,705, JP 10017431, WO 95/35103, JP 09067253, WO92/09262, JP 62093215, and JP 08193094; saponins such as those describedin EP 0,558,509 to Bonte et al., published Sep. 8, 1993 and WO 97/01346to Bonte et al., published Jan. 16, 1997, proteoglycanase orglycosaminoglycanase inhibitors such as those described in U.S. Pat.Nos. 5,015,470, 5,300,284, and 5,185,325, estrogen agonists andantagonists, pseudoterins, cytokine and growth factor promoters, analogsor inhibitors such as interleukin1 inhibitors, interleukin-6 inhibitors,interleukin-10 promoters, and tumor necrosis factor inhibitors, vitaminssuch as vitamin D analogs and parathyroid hormone antagonists, VitaminB12 analogs and panthenol, interferon agonists and antagonists,hydroxyacids such as those described in U.S. Pat. No. 5,550,158,benzophenones, and hydantoin anticonvulsants such as phenytoin, andcombinations thereof.

Other additional hair growth stimulants are described in JP 09-157,139to Tsuji et al., published Jun. 17, 1997; EP 0277455 Al to Mirabeau,published Aug. 10, 1988; WO 97/05887 to Cabo Soler et al., publishedFeb. 20, 1997; WO 92/16186 to Bonte et al., published Mar. 13, 1992; JP62-93215 to Okazaki et al., published Apr. 28, 1987; U.S. Pat. No.4,987,150 to Kurono et al., issued Jan. 22, 1991; JP 290811 to Ohba etal., published Oct. 15, 1992; JP 05-286,835 to Tanaka et al., publishedNov. 2, 1993, FR 2,723,313 to Greff, published Aug. 2, 1994, U. S. Pat.No. 5,015,470 to Gibson, issued May 14, 1991, U.S. Pat. No. 5,559,092,issued Sep. 24, 1996, U.S. Pat. No. 5,536,751, issued Jul. 16, 1996,U.S. Pat. No. 5,714,515, issued Feb. 3, 1998, EPA 0,319,991, publishedJun. 14, 1989, EPA 0,357,630, published Oct. 6, 1988, EPA 0,573,253,published Dec. 8, 1993, JP 61-260010, published Nov. 18, 1986, U.S. Pat.No. 5,772,990, issued Jun. 30, 1998, U.S. Pat. No. 5,053, 410, issuedOct. 1, 1991, and U.S. Pat. No. 4,761,401, issued Aug. 2, 1988.

The most preferred activity enhancers are minoxidil and finasteride,most preferably minoxidil.

Component ii) is a penetration enhancer that can be added to all of thecompositions for systemic administration. The amount of component ii),when present in the composition, is typically 1 to 5%. Examples ofpenetration enhancers include 2-methyl propan-2-ol, propan-2-ol,ethyl-2-hydroxypropanoate, hexan-2,5-diol, polyoxyethylene(2) ethylether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone,polyoxyethylene(2) methyl ether, 2-hydroxypropionic acid,2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran,butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15stearyl ether, octyl alcohol, polyoxyethylene ester of oleyl alcohol,oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate,di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethylsebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctylazelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethylmyristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecylphthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropylpalmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, isopropylisostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyllaurate, ethyl caprate, ethyl caprylate, butyl stearate, benzylsalicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, dimethylsulfoxide, N,N-dimethyl acetarnide, N,N-dimethyl formamide,2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides,sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide,1-dodecylazacyloheptan-2-one, omega three fatty acids and fish oils, andcombinations thereof.

In a preferred embodiment of the invention, the prostaglandins aretopically administered. Topical compositions that can be applied locallyto the skin may be in any form including solutions, oils, creams,ointments, gels, lotions, shampoos, leave-on and rinse-out hairconditioners, milks, cleansers, moisturizers, sprays, skin patches, andthe like. Topical compositions comprise: component A) the prostaglandindescribed above and component B) a carrier. The carrier of the topicalcomposition preferably aids penetration of the prostaglandins into theskin to reach the environment of the hair follicle. Topical compositionspreferably further comprise C) one or more of the optional activityenhancers described above.

The exact amounts of each component in the topical composition fortreating hair loss depend on various factors. The amount of component A)depends on the IC₅₀ of the prostaglandin selected. “IC₅₀” meansinhibitory concentration 50^(th) percentile. The amount of component A)added to the topical composition is:IC ₅₀×10⁻²≧% of component A)≧IC ₅₀×10⁻³,where IC₅₀ is expressed in nanomolar units. For example, if the IC₅₀ ofthe prostaglandin is 1 nM, the amount of component A) will be 0.001 to0.01%. If the IC₅₀ of the prostaglandin is 10 nM, the amount ofcomponent A) will be 0.01 to 0.1%. If the IC₅₀ of the prostaglandin is100 nM, the amount of component A) will be 0.1 to 1.0%. If the IC₅₀ ofthe prostaglandin is 1000 nM, the amount of component A) will be 1.0 to10%, preferably 1.0 to 5%. If the amount of component A) is outside theranges specified above (i.e., either higher or lower), efficacy of thetreatment may be reduced. IC₅₀ can be calculated according to the methodin Reference Example 1, below. One skilled in the art can calculate IC₅₀without undue experimentation.

The topical composition preferably further comprises 1 to 20% componentC), and a sufficient amount of component B) such that the amounts ofcomponents A), B), and C), combined equal 100%. The amount of B) thecarrier employed in conjunction with the prostaglandin is sufficient toprovide a practical quantity of composition for administration per unitdose of the compound. Techniques and compositions for making dosageforms useful in the methods of this invention are described in thefollowing references: Modern Pharmaceutics, Chapters 9 and 10, Banker &Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms:Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms,2^(nd) Ed., (1976).

Component B) the carrier may comprise a single ingredient or acombination of two or more ingredients. In the topical compositions,component B) is a topical carrier. Preferred topical carriers compriseone or more ingredients selected from the group consisting of water,alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils,mineral oil, propylene glycol, polypropylene glycol-2 myristylpropionate, dimethyl isosorbide, combinations thereof, and the like.More preferred carriers include propylene glycol, dimethyl isosorbide,and water.

The topical carrier may comprise one or more ingredients selected fromthe group consisting of q) emollients, r) propellants, s) solvents, t)humectants, u) thickeners, v) powders, and w) fragrances in addition to,or instead of, the preferred topical carrier ingredients listed above.One skilled in the art would be able to optimize carrier ingredients forthe topical compositions without undue experimentation.

Ingredient q) is an emollient. The amount of ingredient q) in thetopical composition is typically 5 to 95%. Suitable emollients includestearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate,propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropylisostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleylalcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol,isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropylmyristate, isopropyl palmitate, isopropyl stearate, butyl stearate,polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconutoil, arachis oil, castor oil, acetylated lanolin alcohols, petrolatum,mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyllinoleate, lauryl lactate, myristyl lactate, decyl oleate, myristylmyristate, polydimethylsiloxane, and combinations thereof. Preferredemollients include stearyl alcohol and polydimethylsiloxane.

Ingredient r) is a propellant. The amount of ingredient r) in thetopical composition is typically 5 to 95%. Suitable propellants includepropane, butane, isobutane, dimethyl ether, carbon dioxide, nitrousoxide, and combinations thereof.

Ingredient s) is a solvent. The amount of ingredient s) in the topicalcomposition is typically 5 to 95%. Suitable solvents include water,ethyl alcohol, methylene chloride, isopropanol, castor oil, ethyleneglycol monoethyl ether, diethylene glycol monobutyl ether, diethyleneglycol monoethyl ether, dimethylsulfoxide, dimethyl formamide,tetrahydrofuran, and combinations thereof. Preferred solvents includeethyl alcohol.

Ingredient t) is a humectant. The amount of ingredient t) in the topicalcomposition is typically 5 to 95%. Suitable humectants include glycerin,sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutylphthalate, gelatin, and combinations thereof. Preferred humectantsinclude glycerin.

Ingredient u) is a thickener. The amount of ingredient u) in the topicalcomposition is typically 0 to 95%.

Ingredient v) is a powder. The amount of ingredient v) in the topicalcomposition is typically 0 to 95%. Suitable powders include chalk, talc,fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodiumpolyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammoniumsmectites, chemically modified magnesium aluminum silicate, organicallymodified montmorillonite clay, hydrated aluminum silicate, fumed silica,carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycolmonostearate, and combinations thereof.

Ingredient w) is a fragrance. The amount of ingredient w) in the topicalcomposition is typically 0.001 to 0.5%, preferably 0.001 to 0.1%.

Component C) the optional activity enhancer is as described above. Anyof the i) hair growth stimulants and ii) penetration enhancers may beadded to the topical compositions. Preferably, the topical compositioncomprises 0.01 to 15% of component i) the optional hair growthstimulant. More preferably, the composition comprises 0.1 to 10%, andmost preferably 0.5 to 5% of component i). Preferably, the topicalcomposition comprises 1 to 5% of component ii).

In an alternative embodiment of the invention, the topical compositionmay be applied to growing hair and skin in the locus of the growing hairto darken to darken hair, reverse hair graying, and thicken the hair.For example, the topical composition may be applied to hair growing onthe scalp or eyelashes. The topical composition can be, for example, acosmetic composition prepared as described above. An example of acomposition that may be applied to eyelashes is a mascara. Theprostaglandin may be added to mascara compositions known in the art,such as the mascara described in U.S. Pat. No. 5,874,072, which ishereby incorporated by reference. The mascara comprises dd) awater-insoluble material, ee) a water-soluble, film-forming polymer, ff)a wax, o) a surfactant, gg) a pigment, and s) a solvent.

Ingredient dd) is a water-insoluble material selected from the groupconsisting of acrylate copolymers; styrene/acrylate/methacrylatecopolymers; acrylic latex; styrene/acrylic ester copolymer latex;polyvinylacetate latex; vinyl acetate/ethylene copolymer latex;styrene/butadiene copolymer latex; polyurethane latex;butadiene/acrylonitrile copolymer latex; styrene/acrylate/acrylonitrilecopolymer latex; and mixtures thereof, wherein the acrylate copolymers,and the styrene/acrylate/rnethacrylate copolymers additionally compriseammonia, propylene glycol, a preservative and a surfactant.

Ingredient ee) is a water-soluble, film-forming polymer. Ingredient ee)is selected from the group consisting of vinylalcohol/poly(alkyleneoxy)acrylate, vinyl alcohol/vinylacetate/poly-(alkyleneoxy)acrylate, polyethylene oxide, polypropyleneoxide, acrylates/octyl-acrylamide copolymers and mixtures thereof.

Ingredient ff) is a wax. “Wax” means a lower-melting organic mixture orcompound of high molecular weight, solid at room temperature andgenerally similar in composition to fats and oils except that theycontain no glycerides. Some are hydrocarbons, others are esters of fattyacids and alcohols. Waxes useful in this invention are selected from thegroup consisting of animal waxes, vegetable waxes, mineral waxes,various fractions of natural waxes, synthetic waxes, petroleum waxes,ethylenic polymers, hydrocarbon types such as Fischer-Tropsch waxes,silicone waxes, and mixtures thereof wherein the waxes have a meltingpoint between 55 and 100° C.

Ingredient o) is surfactant, as described above. Ingredient o) in themascara is preferably a surfactant having an HLB from 3 to 15. Suitablesurfactants include those disclosed in the C.T.F.A. Cosmetic IngredientHandbook, pp. 587-592 (1992); Remington's Pharmaceutical Sciences, 15thEd., pp. 335-337 (1975); and McCutcheon's Volume 1, Emulsifiers &Detergents, North American Edition, pp. 236-239 (1994).

Ingredient gg) is a pigment. Suitable pigments include inorganicpigments, organic lake pigments, pearlescent pigments, and mixturesthereof. Inorganic pigments useful in this invention include thoseselected from the group consisting of rutile or anatase titaniumdioxide, coded in the Color Index under the reference Cl 77,891; black,yellow, red and brown iron oxides, coded under references CI 77,499,77,492 and, 77,491; manganese violet (CI 77,742); ultramarine blue (CI77,007); chromium oxide (Cl 77,288); chromium hydrate (CI 77,289); andferric blue (CI 77,510) and mixtures thereof.

The organic pigments and lakes useful in this invention include thoseselected from the group consisting of D&C Red No. 19 (CI 45,170), D&CRed No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&CRed No. 13 (CI 15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6 (Cl15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36 (CI 12,085), D&COrange No. 10 (CI 45,425), D&C Yellow No. 6 (Cl 15,985), D&C Red No. 30(CI 73,360), D&C Red No. 3 (CI 45,430), and the dye or lakes based onCochineal Carmine (CI 75,570) and mixtures thereof.

The pearlescent pigments useful in this invention include those selectedfrom the group consisting of the white pearlescent pigments such as micacoated with titanium oxide, bismuth oxychloride, colored pearlescentpigments such as titanium mica with iron oxides, titanium mica withferric blue, chromium oxide and the like, titanium mica with an organicpigment of the above-mentioned type as well as those based on bismuthoxychloride and mixtures thereof.

Ingredient s) is a solvent described above, preferably water.

The amount of A) the prostaglandin added to the mascara is as describedabove for topical compositions.

The prostaglandins may also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles, and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines. A preferred formulation for topical delivery ofthe present compounds uses liposomes as described in Dowton et al.,“Influence of Liposomal Composition on Topical Delivery of EncapsulatedCyclosporin A: I. An in vitro Study Using Hairless Mouse Skin”, S.T.P.Pharma Sciences, Vol. 3, pp. 404-407 (1993); Wallach and Philippot, “NewType of Lipid Vesicle: Novasome®”, Liposome Technology, Vol. 1, pp.141-156 (1993); Wallach, U.S. Pat. No. 4,911,928, assigned to Micro-Pak,Inc., issued Mar. 27, 1990; and Weiner et al., U.S. Pat. No. 5,834,014,assigned to The University of Michigan and Micro-Pak, Inc., issued Nov.10, 1998 (with respect to Weiner et al., with a compound as describedherein administered in lieu of, or in addition to, minoxidil).

The prostaglandins may also be administered by iontophoresis. See, e.g.,Internet site www.unipr.it/arpa/dipfarm/erasmus/erasm14.html; Banga etal., “Hydrogel-based lontotherapeutic Delivery Devices for TransdermalDelivery of Peptide/Protein Drugs”, Pharm. Res., Vol. 10 (5), pp.697-702 (1993); Ferry, “Theoretical Model of lontophoresis Utilized inTransdermal Drug Delivery”, Pharmaceutical Acta Helvetiae, Vol 70, pp.279-287 (1995); Gangarosa et al., “Modem lontophoresis for Local DrugDelivery”, Int. J. Pharm., Vol. 123, pp. 159-171 (1995); Green et al.,“Iontophoretic Delivery of a Series of Tripeptides Across the Skin invitro”, Pharm. Res., Vol 8, pp. 1121-1127 (1991); Jadoul et al.,“Quantification and Localization of Fentanyl and TRH Delivered bylontophoresis in the Skin”, Int. J. Pharm., Vol. 120, pp. 221-8 (1995);O'Brien et al., “An Updated Review of its Antiviral Activity,Pharmacokinetic Properties and Therapeutic Efficacy”, Drugs, Vol. 37,pp. 233-309 (1989); Parry et al., “Acyclovir Biovailability in HumanSkin”, J. Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992); Santi etal., “Drug Reservoir Composition and Transport of Salmon Calcitonin inTransdermal lontophoresis”, Pharm. Res., Vol 14 (1), pp. 63-66 (1997);Santi et al., “Reverse lontophoresis—Parameters DeterminingElectroosmotic Flow: I. pH and Ionic Strength”, J. Control. Release,Vol. 38, pp. 159-165 (1996); Santi et al., “Reverselontophoresis—Parameters Determining Electroosmotic Flow: II. ElectrodeChamber Formulation”, J. Control. Release, Vol. 42, pp. 29-36 (1996);Rao et al., “Reverse lontophoresis: Noninvasive Glucose Monitoring invivo in Humans”, Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995);Thysman et al., “Human Calcitonin Delivery in Rats by lontophoresis”, J.Pharm. Pharmacol., Vol. 46, pp. 725-730 (1994); and Volpato et al.,“Iontophoresis Enhances the Transport of Acyclovir through Nude MouseSkin by Electrorepulsion and Electroosmosis”, Pharm. Res., Vol. 12 (11),pp. 1623-1627 (1995).

The prostaglandins may be included in kits comprising a prostaglandin, asystemic or topical composition described above, or both; andinformation, instructions, or both that use of the kit will providetreatment for hair loss in mammals (particularly humans). Theinformation and instructions may be in the form of words, pictures, orboth, and the like. In addition or in the alternative, the kit maycomprise a prostaglandin, a composition, or both; and information,instructions, or both, regarding methods of application of theprostaglandin or composition, preferably with the benefit of treatinghair loss in mammals.

Bone Disorders

In addition to benefits in treating hair loss, the prostaglandins ofthis invention may also be useful to treat bone disorders. Withoutwishing to be bound by theory, it is believed that the prostaglandinsare useful in increasing bone volume and trabecular number throughformation of new trabeculae, formation of bone mass while maintaining anormalized bone turnover rate, and formation at the endosteal surfacewithout removing bone from the existing cortex.

This invention further relates to compositions for treating bonedisorders. Compositions for treating bone disorders can be prepared bystandard pharmaceutical formulation techniques, such as those disclosedin Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Penn. (1990), using the ingredients described above. The preferredroutes of administration for treating bone disorders are transdermal,intranasal, rectal, sublingual, and oral.

Suitable oral compositions for treating bone disorders typicallycomprise A) a prostaglandin described above and B) a carrier. A typicaltablet composition comprises A) the prostaglandin and B) a carriercomprising ingredients selected from the group consisting of a)diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f)flavors, g) sweeteners, k) glidants, and combinations thereof. Preferreddiluents include calcium carbonate, sodium carbonate, mannitol, lactose,and sucrose. Preferred lubricants include magnesium stearate, stearicacid, and talc. Preferred binders include microcrystalline cellulose,starch, and gelatin. Preferred disintegrants include sodium starchglycolate, alginic acid, and croscarmelose.

Typical parenteral pharmaceutical compositions for treating bonedisorders comprise A) the prostaglandin and B) a carrier comprisingingredients selected from the group consisting of j) preservatives andm) solvents. Preferred preservatives include methyl paraben and ethylparaben. Preferred solvents include isotonic saline. One skilled in theart can optimize ingredients for the compositions to treat bonedisorders without undue experimentation.

The prostaglandins can optionally be used in combination with otheringredients which have a beneficial effect on bone loss. Thus, otheractives such as vitamin D analogs, hormones, calcium supplements,diphosphonate compounds such as those extensively described in theliterature of the Procter & Gamble Company, combinations thereof, andthe like may also be administered to patients in need of such treatmentin conjunction with the prostaglandins. Dosage levels and means ofadministration include pulsed-dosing, and are as described in theliterature.

Intraocular Pressure

The prostaglandins used in this invention are also useful in decreasingintraocular pressure. Thus, these prostaglandins are useful in thetreatment of glaucoma. This invention further relates to compositionsfor lowering intraocular pressure. The preferred route of administrationfor lowering intraocular pressure is topical. Topical pharmaceuticalcompositions for ocular administration typically comprise A) aprostaglandin, B) a carrier, such as purified water, and one or moreingredients selected from the group consisting of y) sugars such asdextrans, particularly dextran 70, z) cellulose or a derivative thereof,aa) a salt, bb) disodium EDTA (Edetate disodium), and cc) a pH adjustingadditive.

Examples of z) cellulose derivatives suitable for use in the topicalpharmaceutical composition for ocular administration include sodiumcarboxymethyl cellulose, ethyl cellulose, methyl cellulose, andhydroxypropylmethylcellulose. Hydroxypropylmethylcellulose is preferred.

Examples of aa) salts suitable for use in the for use in the topicalpharmaceutical composition for ocular administration include sodiumchloride, potassium chloride, and combinations thereof.

Examples of cc) pH adjusting additives include HCl or NaOH in amountssufficient to adjust the pH of the topical pharmaceutical compositionfor ocular administration to 7.2-7.5.

Methods of the Invention Hair Loss

This invention further relates to a method for treating hair loss inmammals. The method comprises administering to a mammal (preferably ahuman) suffering from hair loss, a prostaglandin described above. Forexample, a mammal diagnosed with alopecia including male patternbaldness and female pattern baldness can be treated by the methods ofthis invention. Preferably, a systemic or topical composition comprisingA) the prostaglandin and B) a carrier is administered to the mammal.More preferably, the composition is a topical composition comprising A)the prostaglandin, B) the carrier, and C) an optional activity enhancer.

The dosage of the prostaglandin administered to treat hair loss dependson the method of administration. For systemic administration, (e.g.,oral, rectal, nasal, sublingual, buccal, or parenteral), typically, 0.5mg to 300 mg, preferably 0.5 mg to 100 mg, more preferably 0.1 mg to 10mg, of a prostaglandin described above is administered per day. Thesedosage ranges are merely exemplary, and daily administration can beadjusted depending on various factors. The specific dosage of theprostaglandin to be administered, as well as the duration of treatment,and whether the treatment is topical or systemic are interdependent. Thedosage and treatment regimen will also depend upon such factors as thespecific prostaglandin used, the treatment indication, the efficacy ofthe compound, the personal attributes of the subject (such as, forexample, weight, age, sex, and medical condition of the subject),compliance with the treatment regimen, and the presence and severity ofany side effects of the treatment.

For topical administration (e.g., local application on the skin,liposome delivery systems, or iontophoresis), the topical composition istypically administered once per day. The topical compositions areadministered daily for a relatively short amount of time (i.e., on theorder of weeks). Generally, 6 to 12 weeks is sufficient. The topicalcompositions are preferably leave-on compositions. In general, thetopical composition should not be removed for at least several hoursafter administration.

In addition to the benefits in treating hair loss, the inventors havefound that the prostaglandins in the compositions and methods of thisinvention also darken and thicken hair and may reverse hair graying.This invention further relates to a method for darkening hair,thickening hair, and reversing hair graying. The method comprisesapplying the topical composition for treating hair loss to hair, to skinin the locus of hair, or both. In a preferred embodiment of theinvention, the topical composition, such as the mascara compositiondescribed above, is applied to eyelashes.

Bone Disorders

This invention further relates to methods for treating bone disordersusing the prostaglandins described above. The method comprisesadministering to a mammal (preferably a human) suffering from a bonedisorder, a prostaglandin described above. For example, a mammaldiagnosed with osteoporosis can be treated by the methods of thisinvention. Preferably, a systemic composition comprising A) theprostaglandin and B) a carrier is administered to the mammal. Thepreferred routes of administration for treating bone disorders aretransdermal, intranasal, rectal, sublingual, and oral.

The dosage range of the prostaglandin for systemic administration totreat bone disorders is from about 0.01 to about 1000 μg/kg body weight,preferably from about 0.1 to about 100 μg/kg per body weight, mostpreferably form about 1 to about 50 μg/kg body weight per day. Thetransdermal dosages will be designed to attain similar serum or plasmalevels, based upon techniques known to those skilled in the art ofpharmacokinetics and transdermal formulations. Plasma levels forsystemic administration are expected to be in the range of 0.01 to 100nanograms/ml, more preferably from 0.05 to 50 ng/ml, and most preferablyfrom 0.1 to 10 ng/ml. While these dosages are based upon a dailyadministration rate, weekly or monthly accumulated dosages may also beused to calculate the clinical requirements.

Dosages may be varied based on the patient being treated, the conditionbeing treated, the severity of the condition being treated, the route ofadministration, etc. to achieve the desired effect.

Intraocular Pressure

The prostaglandins of the present invention are also useful indecreasing intraocular pressure. Thus, these prostaglandins are usefulin the treatment of glaucoma. This invention further relates to a methodfor lowering intraocular pressure in mammals. The method comprisesadministering to a mammal (preferably a human) a prostaglandin describedabove. For example, a mammal diagnosed with glaucoma can be treated bythe methods of this invention. The preferred route of administration fortreating glaucoma is topical. Preferably, a topical composition forocular administration described above is administered to the mammal. Thetopical composition for ocular administration is typically administeredonce per day. The topical compositions are administered daily for arelatively short amount of time (i.e., on the order of weeks).Generally, 6 to 12 weeks is sufficient.

EXAMPLES

These examples are intended to illustrate the invention to those skilledin the art and should not be interpreted as limiting the scope of theinvention set forth in the claims.

Reference Example 1 Radioligand Binding Assay

IC₅₀ of a prostaglandin can be determined relative to PGF_(2α) using theRadioligand Binding Assay. As a control, the IC₅₀ for PGF_(2α) itselfshould be no lower than 1.0 nM and no higher than 5.0 nM.

In this assay, COS-7 cells are transiently transfected with the hFPrecombinant plasmid using lipofectAMINE Reagent. Forty-eight hourslater, the tranfected cells are washed with Hank's Balanced SaltSolution (HBSS, without CaCl₂, MgCl₂, MgSO₄, or phenol red). The cellsare detached with versene, and HBSS is added. The mixture is centrifugedat 200 g for 10 minutes, at 4° C. to pellet the cells. The pellet isresuspended in Phosphate-Buffered Saline-EDTA buffer (PBS; 1 mM EDTA; pH7.4; 4° C.). The cells are disrupted by nitrogen cavitation (Parr model4639), at 800 psi, for 15 minutes at 4° C. The mixture is centrifuged at1000 g for 10 minutes at 4° C. The supernatant is centrifuged at 100,000g for 60 minutes at 4° C. The pellet is resuspended to 1 mg protein/mLTME buffer (50 mM Tris; 10 mM MgCl2; 1 mM EDTA; pH 6.0; 4° C.) based onprotein levels measured using the Pierce BCA Protein Assay kit. Thehomogenate is mixed for 10 seconds using a Kinematica POLYTRON ®(available from KINEMATICA AG, Luzernerstrasse147A CH-6014 Littau,Switzerland). The membrane preparations are then stored at −80° C.,until thawed for assay use.

The receptor competition binding assays are developed in a 96 wellformat. Each well contains 100 g of hFP membrane, 5 nM (3 H) PGF2α, andthe various competing compounds in a total volume of 200 L. The platesare incubated at 23° C. for 1 hour. The incubation is terminated byrapid filtration using the Packard Filtermate 196 harvester throughPackard UNFILTER® GF/B filters (available from Packard Instrument Co.,Inc. of Downers Grove Ill.) pre-wetted with TME buffer. The filter iswashed four times with TME buffer. Packard Microscint 20, a highefficiency liquid scintillation cocktail, is added to the filter platewells and the plates remain at room temperature for three hours prior tocounting. The plates are read on a Packard TOPCOUNT® MicroplateScintillation Counter (also available from Packard Instrument Co., Inc.)

Reference Example 2 Telogen Conversion Assay

Prostaglandins are tested for their potential to grow hair using theTelogen Conversion Assay. The Telogen Conversion Assay measures thepotential of a prostaglandin to convert mice in the resting stage of thehair growth cycle (“telogen”), to the growth stage of the hair growthcycle (“anagen”).

Without intending to be limited by theory, there are three principalphases of the hair growth cycle: anagen, catagen, and telogen. It isbelieved that there is a longer telogen period in C3H mice (HarlanSprague Dawley, Inc., Indianapolis, Ind.) from approximately 40 days ofage until about 75 days of age, when hair growth is synchronized. It isbelieved that after 75 days of age, hair growth is no longersynchronized. Wherein about 40 day-old mice with dark fur (brown orblack) are used in hair growth experiments, melanogenesis occurs alongwith hair (fur) growth wherein the topical application of hair growthinducers are evaluated. The Telogen Conversion Assay herein is used toscreen prostaglandins for potential hair growth by measuringmelanogenesis.

Three groups of 44 day-old C3H mice are used: a vehicle control group, apositive control group, and a test prostaglandin group, wherein the testprostaglandin group is administered a prostaglandin used in the methodof this invention. The length of the assay is 24 days with 15 treatmentdays (wherein the treatment days occur Mondays through Fridays). Day 1is the first day of treatment. A typical study design is shown in Table4 below. Typical dosage concentrations are set forth in Table 3, howeverthe skilled artisan will readily understand that such concentrations maybe modified. TABLE 4 Assay Parameters Group Animal Con- ApplicationLength # # Compound centration volume of Study 1  1-10 Test 0.01% in 400μL topical 26 days Compound vehicle** 2 11-20 Positive 0.01% in 400 μLtopical 26 days Control vehicle** (T3)* 3 21-30 Vehicle** N/A 400 μLtopical 26 days*T3 is 3,5,3′-triiodothyronine.**The vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethylisosorbide (commercially available from Sigma Chemical Co., St. Louis,MO).

The mice are treated topically Monday through Friday on their lower back(base of tail to the lower rib). A pipettor and tip are used to deliver400 μL to each mouse's back. The 400 μL application is applied slowlywhile moving hair on the mouse to allow the application to reach theskin.

While each treatment is being applied to the mouse topically, a visualgrade of from 0 to 4 will be given to the skin color in the applicationarea of each animal. As a mouse converts from telogen to anagen, itsskin color will become more bluish-black. As indicated in Table 5, thegrades 0 to 4 represent the following visual observations as the skinprogresses from white to bluish-black. TABLE 5 Evaluation CriteriaVisual Observation Grade Whitish Skin Color 0 Skin is light gray(indication of initiation of anagen) 1 Appearance of Blue Spots 2 BlueSpots are aggregating to form one large blue area 3 Skin is dark blue(almost black) with color covering majority of 4 treatment area(indication of mouse in full anagen)

Reference Example 3 Ovariectomized Rat Assay

Bone activity of the prostaglandins can be conveniently demonstratedusing an assay designed to test the ability of the prostaglandins toincrease bone volume, mass, or density. An example of such assays is theovariectomized rat assay.

In the ovariectomized rat assay, six-month old rats are ovariectomized,aged 2 months, and then dosed once a day subcutaneously with aprostaglandin. Upon completion of the study, bone mass and/or densitycan be measured by dual energy x-ray absorptometry (DXA) or peripheralquantitative computed tomography (pQCT), or micro computed tomography(mCT). Alternatively, static and dynamic histomorphometry can be used tomeasure the increase in bone volume or formation.

Reference Example 4 Pharmacological Activity for Glaucoma Assay

Pharmacological activity for glaucoma can be demonstrated using assaysdesigned to test the ability of the subject compounds to decreaseintraocular pressure. Examples of such assays are described in thefollowing reference, incorporated herein: C. liljebris, G. Selen, B.Resul, J. Sternschantz, and U. Hacksell, “Derivatives of17—Phenyl-18,19,20-trinorprostaglandin F₂α Isopropyl Ester: PotentialAntiglaucoma Agents”, Journal of Medicinal Chemistry, Vol. 38 No. 2(1995), pp. 289-304.

Example 1

Compositions for topical administration are made, comprising: Component1-1 1-2 Prostaglandin (wt %) 0.42 1.14 IC₅₀ the PGF (nM) 42 114 Ethanol(wt %) 59.74 59.32 Propylene Glycol (wt %) 19.92 19.77 DimethylIsosorbide (wt %) 19.92 19.77

The prostaglandins in the topical compositions are as follows: ExampleProstaglandin 1-1

1-2

A human male subject suffering from male pattern baldness is treated bya method of this invention. Specifically, for 6 weeks, one of the abovecompositions is daily administered topically to the subject to inducehair growth.

Example 2

A composition for topical administration is made according to the methodof Dowton et al., “Influence of Liposomal Composition on TopicalDelivery of Encapsulated Cyclosporin A: I. An in vitro Study UsingHairless Mouse Skin”, S.T.P. Pharma Sciences, Vol. 3, pp. 404-407(1993), using a PGF in lieu of cyclosporin A and using the NOVASOME® 1(available from Micro-Pak, Inc. of Wilmington, Del.) for the non-ionicliposomal formulation.

A human male subject suffering from male pattern baldness is treatedeach day with the above composition. Specifically, for 6 weeks, theabove composition is administered topically to the subject.

Example 3

Shampoos are made, comprising: Component Ex. 3-1 Ex. 3-2 Ex. 3-3 Ex. 3-4Ammonium Lauryl Sulfate 11.5%   11.5%   9.5%   7.5%   Ammonium LaurethSulfate 4% 3% 2% 2% Cocamide MEA 2% 2% 2% 2% Ethylene Glycol Distearate2% 2% 2% 2% Cetyl Alcohol 2% 2% 2% 2% Stearyl Alcohol 1.2%   1.2%  1.2%   1.2%   Glycerin 1% 1% 1% 1% Polyquaternium 10 0.5%   0.25%   — —Polyquaternium 24 — — 0.5%   0.25%   Sodium Chloride 0.1%   0.1%  0.1%   0.1%   Sucrose Polyesters of Cottonate Fatty Acid 3% 3% — —Sucrose Polyesters of Behenate Fatty Acid 2% 3% — — PolydimethylSiloxane — — 3% 2% Cocaminopropyl Betaine — 1% 3% 3% Lauryl DimethylAmine Oxide 1.5%   1.5%   1.5%   1.5%   Decyl Polyglucose — — 1% 1% DMDMHydantoin 0.15%   0.15%   0.15%   0.15%   PGF having IC₅₀ of 42 nM —0.42%   0.42%   — PGF having IC₅₀ of 114 nM 0.11%   — — 0.11%  Minoxidil 3% 2% Phenoxyethanol 0.5%   0.5%   0.5%   0.5%   Fragrance0.5%   0.5%   0.5%   0.5%   Water q.s. q.s. q.s. q.s.The prostaglandins are the same as in Example 1.

A human subject suffering from male pattern baldness is treated by amethod of this invention. Specifically, for 12 weeks, a shampoodescribed above is used daily by the subject.

Example 4

A mascara composition is prepared The composition comprises: Component %W/W WATER, DEIONIZED, USP q.s. BLACK 1080 MICRONIZED TYPE 10.000GLYCERYL MONOSTEARATE (2400 TYPE) 8.500 C18-36 ACID TRIGLYCERIDE 5.500STEARIC ACID, TRIPLE PRESSED, LIQUID 4.000 ETHYL ALCOHOL SD 40-B, 190PROOF/SERIAL #: 4.000 BEESWAX WHITE, FLAKES 3.250 SHELLAC, NF 3.000LECITHIN, GRANULAR (TYPE 6450) 2.500 TRIETHANOLAMINE 99% - TANK 2.470PARAFFIN WAX 2.250 PARAFFIN WAX 118/125 2.250 CARNAUBA WAX, NF 2.000POTASSIUM CETYL PHOSPHATE 1.000 PHENOXYETHANOL 0.800 OLEIC ACID NF 0.750DL-PANTHENOL 0.350 PVP/VA COPOLYMER 0.250 METHYLPARABEN, NF 0.200DIAZOLIDINYL UREA 0.200 SIMETHICONE 0.200 ETHYLPARABEN NF 0.150PENTAERYTHRITYL HYDROGENATED ROSINATE 0.150 PROPYLPARABEN, NF 0.100TRISODIUM EDTA 0.100 PROSTAGLANDIN having IC₅₀ of 114 nM 0.114The prostaglandin is the same as in Example 1-2.

A human female subject applies the composition each day. Specifically,for 6 weeks, the above composition is administered topically to thesubject to darken and thicken eyelashes.

Example 5

A pharmaceutical composition in the form of a tablet is prepared byconventional methods, such as mixing and direct compaction, formulatedas follows: Ingredient Quantity (mg per tablet) Prostaglandin 5Microcrystalline Cellulose 100 Sodium Starch Glycollate 30 MagnesiumStearate 3

The prostaglandin is the same as in Example 1-2.

When administered orally once daily, the above composition substantiallyincreases bone volume in a patient suffering from osteoporosis.

Example 6

A pharmaceutical compositions in liquid form is prepared by conventionalmethods, formulated as follows: Ingredient Quantity Prostaglandin 1 mgPhosphate buffered physiological saline 10 ml Methyl Paraben 0.05 ml

The prostaglandin used is the same as in Example 1-2.

When 1.0 ml of the above composition is administered subcutaneously oncedaily, the above composition substantially increases bone volume in apatient suffering from osteoporosis.

Example 7

A topical pharmaceutical composition for lowering intraocular pressureare prepared by conventional methods and formulated as follows:Ingredient Amount (wt %) Prostaglandin 0.004 Dextran 70 0.1Hydroxypropyl methylcellulose 0.3 Sodium Chloride 0.77 Potassiumchloride 0.12 Disodium EDTA (Edetate disodium) 0.05 Benzalkoniumchloride 0.01 HCl and/or NaOH pH 7.2-7.5 Purified water q.s. to 100%

The prostaglandin is the same as in Example 1-2.

When the above composition is administered once daily for 6 to 12 weeks,it lowers intraocular pressure in a patient suffering from glaucoma.

Effects of the Invention

The compositions and methods herein provide a cosmetic benefit withrespect to hair growth and appearance in subjects desiring suchtreatment. The compositions and methods herein also providepharmaceutical benefits with respect to treating bone disorders andlowering intraocular pressure in subjects needing such treatment.

1. A method for treating hair loss comprising administering to a mammalsuffering from hair loss, a composition comprising: A) an activeingredient selected from the group consisting of2-decarboxy-2-phosphinico derivatives of prostaglandins; opticalisomers, diastereomers, and enantiomers of the 2-decarboxy-2-phosphinicoderivatives; pharmaceutically-acceptable salts of the2-decarboxy-2-phosphinico derivatives; amides, esters, and imides of the2-decarboxy-2-phosphinico derivatives; and combinations thereof.
 2. Themethod of claim 1, wherein the of 2-decarboxy-2-phosphinico derivativehas a structure selected from the group consisting of:

wherein R¹ is selected from the group consisting of a hydrogen atom, andlower monovalent hydrocarbon groups, and lower heterogeneous groups; R²is selected from the group consisting of a hydrogen atom, a monovalenthydrocarbon group, a substituted monovalent hydrocarbon group, aheterogeneous group, a substituted heterogeneous group, a carbocyclicgroup, a substituted carbocyclic group, a heterocyclic group, asubstituted heterocyclic group, an aromatic group, a substitutedaromatic group, a heteroaromatic group, and a substituted heteroaromaticgroup; R³ is selected from the group consisting of an oxygen atom, asulfur atom, and NH; R⁴ is selected from the group consisting of anoxygen atom and a sulfur atom; R⁵ is a divalent group selected from thegroup consisting of a hydrocarbon group, a substituted hydrocarbongroup, a heterogeneous group, and a substituted heterogeneous group;with the proviso that when R⁵ is a heterogeneous group, R⁵ has only oneheteroatom, which is selected from the group consisting of oxygen,sulfur, and nitrogen; bond a is selected from the group consisting of asingle bond, a trans double bond, and a triple bond; R⁶ is a divalentgroup selected from the group consisting of —C(O)— and —C(R⁹)(OR⁹)—;R⁷is selected from the group consisting of a divalent group having theformula —(CR⁹(R⁹))_(p)—X—(CR⁹(R⁹))_(q), wherein p is an integer from 0to 3 and q is an integer from 0 to 3, and wherein X is selected from thegroup consisting of an oxygen atom, a divalent hydrocarbon group, asulfur atom, SO, SO₂, and NR⁹; R⁸ is selected from the group consistingof a methyl group, a carbocyclic group, a substituted carbocyclic group,a heterocyclic group, a substituted heterocyclic group, aromatic group,a substituted aromatic group, a heteroaromatic group, a substitutedheteroaromatic group; R⁹ is selected from the group consisting of ahydrogen atom and a lower monovalent hydrocarbon group; and R¹⁰ isselected from the group consisting of a hydrogen atom and a lowermonovalent hydrocarbon group.
 3. The method of claim 1, wherein thecomposition is administered by a route selected from the groupconsisting of systemic and topical routes.
 4. The method of claim 3,wherein the composition is a topical composition in a form selected fromthe group consisting of solutions, oils, creams, ointments, gels,lotions, shampoos, leave-on and rinse-out hair conditioners, milks,cleansers, moisturizers, sprays, and skin patches.
 5. The method ofclaim 4, wherein the composition is a topical composition furthercomprising B) a topical carrier, wherein the topical carrier comprisesan ingredient selected from the group consisting of q) emollients, r)propellants, s) solvents, t) humectants, u) thickeners, v) powders, w)fragrances, water, alcohols, aloe vera gel, allantoin, glycerin, vitaminA and E oils, mineral oil, propylene glycol, dimethyl isosorbide,polypropylene glycol-2 myristyl propionate, and combinations thereof. 6.The method of claim 1, wherein the composition further comprises C) anactivity enhancer selected from the group consisting of i) a hair growthstimulant, ii) a penetration enhancer, and combinations thereof.
 7. Themethod of claim 6, wherein component i) is selected from the groupvasodilator, an antiandrogen, a cyclosporin, a cyclosporin analog, anantimicrobial, an anti-inflammatory, a thyroid hormone, a thyroidhormone derivative, and a thyroid hormone analog, a non-selectiveprostaglandin agonist, a non-selective prostaglandin antagonist, aretinoid, a triterpene, and combinations thereof.
 8. The method of claim6, wherein component ii) is selected from the group consisting of2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate,hexan-2,5-diol, polyoxyethylene(2) ethyl ether, di(2-hydroxypropyl)ether, pentan-2,4-diol, acetone, polyoxyethylene(2) methyl ether,2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol,1,4-dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycoldipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol,polyoxyethylene ester of oleyl alcohol, oleyl alcohol, lauryl alcohol,dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropylsebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctylsebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutylphthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butylmyristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethylcaproate, ethyl salicylate, isopropyl palmitate, ethyl laurate,2-ethyl-hexyl pelargonate, isopropyl isostearate, butyl laurate, benzylbenzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate,butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid,2hydroxyoctanoic acid, dimethyl sulfoxide, N,N-dimethyl acetamide,N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone,5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone,1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters,tetrahydrofurfural alcohol, urea, diethyl-m-toluamide,1-dodecylazacyloheptan-2-one, and combinations thereof.
 9. The method ofclaim 3, wherein the composition is a topical composition locallyadministered on the skin once per day.
 10. The method of claim 9,wherein the composition is administered once per day for 6 to 12 weeks.11. The method of claim 1, wherein R²is selected from the groupconsisting of H, CH₂CO₂H, CH₂C(O)NHOH, methyl, CF₃, ethyl, n-propyl,isopropyl, CH₂CH₂OH, CH₂CH(OH)CH₂OH, benzyl, and t-butyl.
 12. The methodof claim 2, wherein R³is selected from the group consisting of an oxygenatom and NH.
 13. The method of claim 2, wherein R⁴is an oxygen atom. 14.The method of claim 2, wherein R⁵ has 1 to 5 member atoms.
 15. Themethod of claim 2, wherein R⁶is —C(H)(OH)—.
 16. The method of claim 2,wherein X is selected from the group consisting of an oxygen atom, asulfur atom, and NR⁹.
 17. The method of claim 2, wherein R⁸is selectedfrom the group consisting of a monocyclic carbocyclic group, asubstituted monocyclic carbocyclic group, a monocyclic heterocyclicgroup, a substituted monocyclic heterocyclic group, aromatic group, asubstituted aromatic group, a heteroaromatic group, and a substitutedheteroaromatic group.
 18. The method of claim 1, wherein R⁹ is ahydrogen atom.
 19. A method for darkening and thickening hair comprisingapplying to growing hair and skin, a composition comprising: A) anactive ingredient selected from the group consisting of2-decarboxy-2-phosphinico derivatives of prostaglandins; opticalisomers, diastereomers, and enantiomers of the 2-decarboxy-2-phosphinicoderivatives; pharmaceutically-acceptable salts of the2-decarboxy-2-phosphinico derivatives; amides, esters, and imides of the2-decarboxy-2-phosphinico derivatives; and combinations thereof; and B)a carrier.
 20. The method of claim 19, wherein the of2-decarboxy-2-phosphinico derivative has a structure selected from thegroup consisting of:

wherein R¹ is selected from the group consisting of a hydrogen atom, andlower monovalent hydrocarbon groups, and lower heterogeneous groups; R²is selected from the group consisting of a hydrogen atom, a monovalenthydrocarbon group, a substituted monovalent hydrocarbon group, aheterogeneous group, a substituted heterogeneous group, a carbocyclicgroup, a substituted carbocyclic group, a heterocyclic group, asubstituted heterocyclic group, an aromatic group, a substitutedaromatic group, a heteroaromatic group, and a substituted heteroaromaticgroup; R³ is selected from the group consisting of an oxygen atom, asulfur atom, and NH; R⁴ is selected from the group consisting of anoxygen atom and a sulfur atom; R⁵ is a divalent group selected from thegroup consisting of a hydrocarbon group, a substituted hydrocarbongroup, a heterogeneous group, and a substituted heterogeneous group;with the proviso that when R⁵ is a heterogeneous group, R⁵ has only oneheteroatom, which is selected from the group consisting of oxygen,sulfur, and nitrogen; bond a is selected from the group consisting of asingle bond, a trans double bond, and a triple bond; R⁶ is a divalentgroup selected from the group consisting of —C(O)— and —C(R⁹)(OR⁹)—; R⁷is selected from the group consisting of a divalent group having theformula —(CR⁹(R⁹))_(p)—X—(CR⁹(R⁹))_(q), wherein p is an integer from 0to 3 and q is an integer from 0 to 3, and wherein X is selected from thegroup consisting of an oxygen atom, a divalent hydrocarbon group, asulfur atom, SO, SO₂, and NR⁹; R⁸ is selected from the group consistingof a methyl group, a carbocyclic group, a substituted carbocyclic group,a heterocyclic group, a substituted heterocyclic group, aromatic group,a substituted aromatic group, a heteroaromatic group, a substitutedheteroaromatic group; R⁹ is selected from the group consisting of ahydrogen atom and a lower monovalent hydrocarbon group; and R¹⁰ isselected from the group consisting of a hydrogen atom and a lowermonovalent hydrocarbon group.